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GSE5827
Homo sapiens
28 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The NOTCH1 signaling pathway directly links extracellular signals with transcriptional responses in the cell nucleus and plays a critical role during T-cell development and in the pathogenesis over 50% of human T-cell lymphoblastic leukemia (T-ALL) cases. However, little is known about the transcriptional programs activated by NOTCH1. Using an integrative systems biology approach we show that NOTCH1 controls a feed-forward loop transcriptional network that promotes cell growth. Inhibition of NOTCH1 signaling in T-ALL cells led to a reduction in cell size and elicited a gene expression signature dominated by downregulated biosynthetic pathway genes. By integrating gene expression array and ChIP-on-chip data, we show that NOTCH1 directly activates multiple biosynthetic routes and induces c-MYC gene expression. Reverse engineering of regulatory networks from expression profiles showed that NOTCH1 and c-MYC govern two directly interconnected transcriptional programs containing common target genes that together regulate the growth of primary T-ALL cells. These results identify c-MYC as an essential mediator of NOTCH1 signaling and integrate NOTCH1 activation with oncogenic signaling pathways upstream of c-MYC.
Publication Title
NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 120 Downloadable Samples
Illumina HumanHT-12 V4.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 72 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Analysis of gene expression in cholangiocarcinoma patients.
Publication Title
Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 48 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Analysis of gene expression in cholangiocarcinoma patients.
Publication Title
Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma.
Sample Metadata Fields
Specimen part
View Samples- Danio rerio
- 6 Downloadable Samples
NextSeq 500
Description
The SWI/SNF-family chromatin remodeling protein ATRX is a tumor suppressor in sarcomas, gliomas and other malignancies. Its loss of function facilitates the alternative lengthening of telomeres (ALT) pathway in tumor cells, while it also affects Polycomb repressive complex 2 (PRC2) silencing of its target genes. To further define the role of inactivating ATRX mutations in carcinogenesis, we knocked out atrx in our previously published p53/nf1-deficient zebrafish line that develops malignant peripheral nerve sheath tumors and gliomas. Complete inactivation of atrx using CRISPR-cas9 was lethal in developing fish and resulted in an alpha-thalassemia-like phenotype including reduced alpha-globin expression. In p53/nf1-deficient zebrafish neither peripheral nerve sheath tumors nor gliomas showed accelerated onset in atrx+/- fish, but these fish developed various tumors that were not observed in their atrx+/+ siblings, including epithelioid sarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma and rare types of carcinoma. Most of these cancer types are included in the AACR Genie database of human tumors associated with mutant ATRX, indicating that our zebrafish model reliably reflects a role for ATRX-loss in the early pathogenesis of these types of human cancers. RNA-seq of p53/nf1- and p53/nf1/atrx-deficient tumors revealed that down-regulation of telomerase accompanied ALT-mediated lengthening of the telomeres in atrx-mutant samples. Moreover, inactivating mutations in atrx disturbed PRC2-target gene silencing, indicating a connection between ATRX loss and PRC2 dysfunction in cancer development. Overall design: Gene expression values were derived from paired end RNA-Seq data that compared zebrafish samples from p53/nf1/atrx-deficient tumors to samples from atrx-wildtype controls (3 vs. 3 samples).
Publication Title
Loss of atrx cooperates with p53-deficiency to promote the development of sarcomas and other malignancies.
Sample Metadata Fields
Subject
View Samples- Homo sapiens
- 65 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Background & Aims: Chronic hepatitis C virus (HCV) infection is complicated by hepatic fibrosis. Hypothesizing that fibrogenic signals may originate in cells susceptible to HCV infection, gene expression of hepatocytes was analyzed from persons with chronic HCV at different stages of liver fibrosis. Methods: HCV-infected subjects with significant liver fibrosis (Ishak fibrosis 3) were matched for age, race, and gender to subjects with minimal fibrosis (Ishak fibrosis 0-1). RNA from portal tracts and hepatic parenchyma was isolated from biopsies by laser capture and transcriptome profiling was performed using hybridization arrays. Results: Portal tracts from both groups were enriched for immune related genes when compared to hepatocytes but high fibrosis subjects showed a loss of this enrichment. Hepatocytes from persons with high fibrosis were depleted for genes involved in small molecule and drug metabolism, especially butyrylcholinesterase (BCHE), a gene involved in the metabolism of drugs of abuse. Differential expression of BCHE was validated in the same tissues using qPCR. Cross-sectional and longitudinal testing in an expanded cohort of HCV-infected individuals showed that serum BCHE activity decreased in advance of progression to fibrosis. Conclusion: Chronic HCV infection is associated with a loss of hepatocyte metabolic function, decreased enrichment of immune-related genes in portal tracts and downregulation of BCHE in hepatocytes. Our results indicate that BCHE may be involved in the progression of fibrosis during HCV infection among injection drug users and may serve as a useful marker for fibrosis progression.
Publication Title
Laser captured hepatocytes show association of butyrylcholinesterase gene loss and fibrosis progression in hepatitis C-infected drug users.
Sample Metadata Fields
Sex, Age, Race
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
NOTCH proteins regulate signaling pathways involved in cellular differentiation, proliferation and death. Overactive Notch signaling as been observed in numerous cancers and has been extensively studied in the context of T-cell acute lymphoblastic leukemia (T-ALL) where more than 50% of pateints harbour mutant NOTCH1. Small molecule modulators of these proteins would be important for understanding the role of NOTCH proteins in malignant and normal biological processes.
Publication Title
Direct inhibition of the NOTCH transcription factor complex.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 11 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Expression of a constitutively active Notch-1 intracellular domain (NICD) in MCF-10A cells was found to induce two distinct types of 3D structures: large, hyperproliferative structures and small, growth-arrested structures with reduced cell-to-matrix adhesion. These heterogeneous phenotypes reflect differences in Notch pathway activation levels. High Notch activity caused loss of cell adhesion and inhibition of proliferation, whereas low Notch activity maintained matrix adhesion and provoked a strong hyperproliferative response. In order to gain insight into the dosage-dependent transcriptional events triggered by Notch1 activation, gene expression profiles induced 48 hours after infection of MCF-10A cells with retroviral vectors expressing full-length Notch-1, L1601P+P, or NICD were compared. Full-length Notch-1 induced the weakest effect, L1601P+P induced an intermediate effect and NICD induced the strongest effect. Results provide insight into the dichotomous activites of Notch during development and tumorigenesis.
Publication Title
Dose-dependent induction of distinct phenotypic responses to Notch pathway activation in mammary epithelial cells.
Sample Metadata Fields
Cell line
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Platelets are a rich source of many cytokines and chemokines including transforming growth factor -1 (TGF1). TGF1 is required to convert conventional CD4+ T (Tconv) cells into induced regulatory T (iTreg) cells that express the transcription factor Foxp3. To explore whether other platelet contents will affect the properties of TGF induced Treg cell, we used platelet lysate that contain many other cytokines and chemokines besides TGF1 (pltTGF) to induce Foxp3 expression (pltTGFb-iTreg) from conventional CD4+ T (Tconv) cells. We used purified TGF1 to induce Treg (purTGF-iTreg) cells as a control. Gene expression profiles in iTreg cells were analyzed by microarray asay.
Publication Title
TGF-β1 along with other platelet contents augments Treg cells to suppress anti-FVIII immune responses in hemophilia A mice.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 8 Downloadable Samples
- Illumina Genome Analyzer IIx
Description
Despite initial and often dramatic responses of epidermal growth factor receptor (EGFR)-addicted lung tumors to the EGFR-specific tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, nearly all develop resistance and relapse. To explore novel mechanisms mediating acquired resistance, we employed non-small-cell lung cancer (NSCLC) cell lines bearing activating mutations in EGFR and rendered them resistant to EGFR-specific TKIs through chronic adaptation in tissue culture. In addition to previously observed resistance mechanisms including EGFR-T790M ''gate-keeper'' mutations and MET amplification, a subset of the seven chronically adapted NSCLC cell lines including HCC4006, HCC2279 and H1650 cells exhibited marked induction of fibroblast growth factor (FGF) 2 and FGF receptor 1 (FGFR1) mRNA and protein. Also, adaptation to EGFR-specific TKIs was accompanied by an epithelial to mesenchymal transition (EMT) as assessed by changes in CDH1, VIM, ZEB1 and ZEB2 expression and altered growth properties in Matrigel. In adapted cell lines exhibiting increased FGF2 and FGFR1 expression, measures of growth and signaling, but not EMT, were blocked by FGFR-specific TKIs, an FGF-ligand trap and FGFR1 silencing with RNAi. In parental HCC4006 cells, cell growth was strongly inhibited by gefitinib, although drug-resistant clones progress within 10 days. Combined treatment with gefitinib and AZD4547, an FGFR-specific TKI, prevented the outgrowth of drug-resistant clones. Thus, induction of FGF2 and FGFR1 following chronic adaptation to EGFR-specific TKIs provides a novel autocrine receptor tyrosine kinase-driven bypass pathway in a subset of lung cancer cell lines that are initially sensitive to EGFR-specific TKIs. The findings support FGFR-specific TKIs as potentially valuable additions to existing targeted therapeutic strategies with EGFR-specific TKIs to prevent or delay acquired resistance in EGFR-driven NSCLC. Overall design: Examination of mRNA levels in DMSO and gefitinib-resistant cultures of HCC4006 and HCC827. Each group has two replicates.
Publication Title
A mechanism of resistance to gefitinib mediated by cellular reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples